Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

Guangfu Li, Dai Liu, Timothy Cooper, Eric T. Kimchi, Xiaoqiang Qi, Diego M. Avella, Ningfei Li, Qing Yang, Mark Kester, C. Bart Rountree, Jussuf T. Kaifi, David J. Cole, Don C. Rockey, Todd Schell, Kevin F. Staveley-O'Carroll

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Background & Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8 + T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8 + T cells associated with accumulation of programmed cell death protein 1 (PD-1) hi CD8 + T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. Lay summary In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

Original languageEnglish (US)
Pages (from-to)75-85
Number of pages11
JournalJournal of Hepatology
Volume66
Issue number1
DOIs
StatePublished - Jan 1 2017

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Liver Neoplasms
Neoplasms
Neoplasm Antigens
T-Lymphocytes
Programmed Cell Death 1 Receptor
Immunity
Circulating Neoplastic Cells
Immune Tolerance
Adoptive Transfer
Antibodies
Carbon Tetrachloride
Regulatory T-Lymphocytes
United States Food and Drug Administration
Intraperitoneal Injections
Protein-Tyrosine Kinases
Immunotherapy
Cell Movement
Hepatocytes
Immune System
Immunization

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Li, G., Liu, D., Cooper, T., Kimchi, E. T., Qi, X., Avella, D. M., ... Staveley-O'Carroll, K. F. (2017). Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. Journal of Hepatology, 66(1), 75-85. https://doi.org/10.1016/j.jhep.2016.07.044
Li, Guangfu ; Liu, Dai ; Cooper, Timothy ; Kimchi, Eric T. ; Qi, Xiaoqiang ; Avella, Diego M. ; Li, Ningfei ; Yang, Qing ; Kester, Mark ; Rountree, C. Bart ; Kaifi, Jussuf T. ; Cole, David J. ; Rockey, Don C. ; Schell, Todd ; Staveley-O'Carroll, Kevin F. / Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. In: Journal of Hepatology. 2017 ; Vol. 66, No. 1. pp. 75-85.
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title = "Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model",
abstract = "Background & Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8 + T cells maintained a na{\"i}ve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8 + T cells associated with accumulation of programmed cell death protein 1 (PD-1) hi CD8 + T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. Lay summary In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.",
author = "Guangfu Li and Dai Liu and Timothy Cooper and Kimchi, {Eric T.} and Xiaoqiang Qi and Avella, {Diego M.} and Ningfei Li and Qing Yang and Mark Kester and Rountree, {C. Bart} and Kaifi, {Jussuf T.} and Cole, {David J.} and Rockey, {Don C.} and Todd Schell and Staveley-O'Carroll, {Kevin F.}",
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Li, G, Liu, D, Cooper, T, Kimchi, ET, Qi, X, Avella, DM, Li, N, Yang, Q, Kester, M, Rountree, CB, Kaifi, JT, Cole, DJ, Rockey, DC, Schell, T & Staveley-O'Carroll, KF 2017, 'Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model', Journal of Hepatology, vol. 66, no. 1, pp. 75-85. https://doi.org/10.1016/j.jhep.2016.07.044

Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model. / Li, Guangfu; Liu, Dai; Cooper, Timothy; Kimchi, Eric T.; Qi, Xiaoqiang; Avella, Diego M.; Li, Ningfei; Yang, Qing; Kester, Mark; Rountree, C. Bart; Kaifi, Jussuf T.; Cole, David J.; Rockey, Don C.; Schell, Todd; Staveley-O'Carroll, Kevin F.

In: Journal of Hepatology, Vol. 66, No. 1, 01.01.2017, p. 75-85.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Successful chemoimmunotherapy against hepatocellular cancer in a novel murine model

AU - Li, Guangfu

AU - Liu, Dai

AU - Cooper, Timothy

AU - Kimchi, Eric T.

AU - Qi, Xiaoqiang

AU - Avella, Diego M.

AU - Li, Ningfei

AU - Yang, Qing

AU - Kester, Mark

AU - Rountree, C. Bart

AU - Kaifi, Jussuf T.

AU - Cole, David J.

AU - Rockey, Don C.

AU - Schell, Todd

AU - Staveley-O'Carroll, Kevin F.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background & Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8 + T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8 + T cells associated with accumulation of programmed cell death protein 1 (PD-1) hi CD8 + T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. Lay summary In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

AB - Background & Aims We have established a clinically relevant animal model of hepatocellular cancer (HCC) in immune competent mice to elucidate the complex dialog between host immunity and tumors during HCC initiation and progression. Mechanistic findings have been leveraged to develop a clinically feasible anti-tumor chemoimmunotherapeutic strategy. Methods Intraperitoneal injection of carbon tetrachloride and intrasplenic inoculation of oncogenic hepatocytes were combined to induce progressive HCCs in fibrotic livers of immunocompetent mice. Immunization and adoptive cell transfer (ACT) were used to dissect the tumor antigen-specific immune response. The ability of the tyrosine kinase inhibitor sunitinib to enhance immunotherapy in the setting of HCC was evaluated. Results This new mouse model mimics human HCC and reflects its typical features. Tumor-antigen-specific CD8 + T cells maintained a naïve phenotype and remained responsive during early-stage tumor progression. Late tumor progression produced circulating tumor cells, tumor migration into draining lymph nodes, and profound exhaustion of tumor-antigen-specific CD8 + T cells associated with accumulation of programmed cell death protein 1 (PD-1) hi CD8 + T cells and regulatory T cells (Tregs). Sunitinib-mediated tumoricidal effect and Treg suppression synergized with antibody-mediated blockade of PD-1 to powerfully suppress tumor growth and activate anti-tumor immunity. Conclusion Treg accumulation and upregulation of PD-1 provide two independent mechanisms to induce profound immune tolerance in HCC. Chemoimmunotherapy using Food and Drug Administration-approved sunitinib with anti-PD-1 antibodies achieved significant tumor control, supporting translation of this approach for the treatment of HCC patients. Lay summary In the current study, we have established a clinically relevant mouse model which mimics human liver cancer. Using this unique model, we studied the response of the immune system to this aggressive cancer. Findings from this trial have led to the development of an innovative and clinically feasible chemoimmunotherapeutic strategy.

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